Activation of the innate immune system upon pathogen recognition results in a rapid and definitive microbicidal response to invading microorganisms that is fine-tuned to prevent deleterious deficiencies or excesses in the response. Increasing evidence indicates that immune responses are rapidly coordinated by neural circuits that operate reflexively. However, given the complexity of the nervous and immune systems of mammals, the precise mechanisms by which the two systems influence each other remain understudied. This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity. Using the nematode Caenorhabditis elegans, we have recently demonstrated that innate immunity is not only regulated at the cell autonomous level, but also at the cell non-autonomous level through neurons expressing G-protein-coupled receptors. More specifically, we found that NPR-1, a GPCR similar to mammalian neuropeptide Y receptors, participates in a neural circuit that controls the p38/PMK-1 MAPK pathway in C. elegans. Additional studies from our laboratory indicate that OCTR-1, which is an adrenergic GPCR for octopamine expressed in the nervous system, controls the p38/PMK-1 pathway and unfolded response pathways that are expressed in non-neuronal tissues and that are necessary to alleviate the increased demand on protein folding during immune activation. In this proposal specifically, we will use a variety of molecular and genetic techniques to explore the general hypothesis that the nervous system regulates immune homeostasis during host response to pathogen infections at the whole animal level. Given the conserved nature of innate immune responses and of GPCR-mediated signaling in the nervous system, the proposed studies should lead to a better understanding of some of the mechanisms by which the metazoan nervous and innate immune systems influence each other.